Influencing factors on morbidity and mortality in intertrochanteric fractures

We aimed to evaluate the effect of the patient’s clinical and paraclinical condition before and after surgery on short-term mortality and complication and long-term mortality. A retrospective cohort study was conducted and multivariate logistic regression was applied to determine the effect of demographic characteristics (sex, age, AO/OTA classification, height, weight, body mass index), medical history (hypertension, ischemic heart disease, diabetes mellitus, thyroid malfunction, cancer, osteoporosis, smoking) lab data (Complete blood cell, blood sugar, Blood Urea Nitrogen, Creatinine, Na, and K), surgery-related factors (Anesthesia time and type, implant, intraoperative blood transfusion, postoperative blood transfusion, and operation time), duration of admission to surgery and anticoagulant consumption on short-term mortality and complication and long-term mortality. Three hundred ten patients from November 2016 to September 2020 were diagnosed with an intertrochanteric fracture. 3.23% of patients died in hospital, 14.1% of patients confronted in-hospital complications, and 38.3% died after discharge till the study endpoint. ΔNumber of Neutrophiles is the primary determinant for in-hospital mortality in multivariate analysis. Age and blood transfusion are the main determinants of long-term mortality, and Na before surgery is the primary variable associated with postoperative complications. Among different analytical factors Na before surgery as a biomarker presenting dehydration was the main prognostic factor for in hospital complications. In hospital mortality was mainly because of infection and long-term mortality was associated with blood transfusion.


Results
During the study period Three hundred ten patients were diagnosed with an intertrochanteric fracture. 270 patients had full-recorded progress notes in which in hospital complication could be assessed (87%). 67 patients lost to follow-up, which results in a sample size of 243 patients for mortality in long term (81%). All post operative complications are presented on Table 1. The percentage of the female population in those who died in hospital, had complications in hospital, and died in log-term after discharge are as follows: 30%, 34.2%, and 59.1%; Also the mean age of those who died in hospital, had complications in hospital, and died in log-term after discharge is 82. 30, 76.37, and 78.55 years respectively. 3.23% of patients died in hospital, 14.1% of patient confront in hospital complication and 38.3% died after discharge till study endpoint. Patients' data are shown in Table 2.
Patients experiencing postoperative complications in the hospital were more likely to have an increased Δ Cr (p = 0.017), Δ BUN (p = 0.099), and Na before surgery (p = 0.022). Patients who died in the long term were more likely to be female (p=0.013), and those with a lower rate of smoking (p=0.008), a lower Hemoglobin before surgery (p=0.000), a lower drop in hemoglobin (p=0.020), longer Duration of admission to surgery (P=0.004), to have Diabetes Mellitus (p=0.004), BUN before surgery (p=0.000), K before surgery (p=0.076), Δ Na (p=0.064), Δ Neutrophile/Lymphocyte (p=0.072), and Blood sugar baseline (p=0.028). Older age, history of HTN or IHD, blood transfusion (before or after surgery), and higher creatine levels before surgery lead to the worse outcome (in hospital mortality, long-term mortality or in hospital complication).  (Fig. 2). The optimal cut-off values for age, BUN before surgery, and Cr before surgery were 78.5 years (sensitivity = 0.900 and specificity = 0.540), 54.5 mg/dL (sensitivity = 0.800 and specificity = 0.703), and 1.43 mg/dL (sensitivity = 0.800 and specificity = 0.859). Age, HTN, IHD, Cr before surgery, Na before surgery, Δ BUN, and blood transfusion are included in the regression model for in-hospital complications. The p-value of the Hosmer and Lameshow test is 0.117. Na before surgery is the main determinant. The model is explained in Table 4. The AUC for age, Cr before surgery, Na before surgery, Δ BUN were all less than 0.70. The predictive model for long-term mortality was obtained by cox regression and ΔHb is excluded due to interaction with hemoglobin before surgery; ΔNa and Δ Neutrophile/lymphocyte were also excluded to reach the fittest model available. Age and blood transfusion are the main determinants. The model is explained in Table 5. The AUC for age (0.720, 95% CI [0.657-0.783]) and Hemoglobin before surgery (0.718, 95% CI [0.652-0.784] were more than 0.70. the optimal cut-off value for age and Hemoglobin before surgery were 74.5 years (sensitivity = 0.72 and specificity = 0.62) and 11.05 mg/ dL (sensitivity = 0.74 and specificity = 0.634) (Fig. 1).
Patients stratified into 4 groups base on blood transfusion status and age. Kaplan-Meier survival curves of four groups are demonstrated. The 54 months survival of total population is 0.51 (SE=0.044) (Fig. 2).

Discussion
The results of our study suggest that a significant rise in number of neutrophile may be associated with in-hospital mortality. Those with increased Na before surgery are more likely to experience in hospital complication. Age is the main determinant of long-term mortality alongside with intra and post-operative blood transfusion.
Post-op neutrophil as a biomarker representing infection was correlated with short-term mortality 19 . Neutrophile count was positively correlated with size of infarction, and Ischemic and non-ischemic heart failure are associated with increased innate leukocytes, and post-op heart failure has a robust association with mortality after hip fracture [19][20][21] . After stroke neutrophil start to degrade blood brain barrier and predispose brain to a second injury and by several mechanism worsens outcome 22 . Furthermore, in acute ischemic strokes, peripheral neutrophil counts are correlated with larger infarct volumes and fatal outcomes 23 . In hypertensive population neutrophil count increase the risk of first stroke and stroke is one of the post-op comorbidities which increase the risk of mortality in those with hip fracture 19,24 .
In a cohort study of Asian population, 14,744 elderly patients with hip fracture were followed up for 11 years. 10973 patients included in the transfusion group and the adjusted relative risk of mortality was 1.64, 1.58, 1.43 for 90 days, 180 days, and 1 year respectively 25 . In our study the adjusted odds ratio of mortality was 1.932 (95% CI [1.023-3.648], p=0.042). It is believed that there might be immunosuppressive consequences with blood transfusion by suppressing CD3 (T-lymphocytes) 26 . This could result in making patients susceptible to infection which is supported by a meta-analysis of 20 studies which reported an odds ratio of 5.263 (range, 5.03-5.43) for bacterial infection in trauma patients while infection is a risk factor of long-term mortality in the study of Roche et al. 19,27,28 . A large blood transfusion may lead to fluid overload in elderly who are small and frail. Comorbidities like HTN, chronic kidney disease, and previous heart failure as predisposing factor in combination with large blood transfusion may lead to iatrogenic heart failure and heart failure is the most important risk factor of long-term mortality after hip fracture 19,29 . To overcome this problem other blood product including iron  www.nature.com/scientificreports/ supplements, Erythropoietin, or anti-fibrinolytics should be considered [30][31][32] . However, in a meta-analysis of 54 studies in 2015 the results don't demonstrate an increased risk of long-term mortality in those with blood transfusion after adjusting for all comorbidities 33 . Further prospective studies with larger sample size are needed to clarify the effect of blood transfusion on long-term mortality. In our study 93 patients (38%) died in long-term and based on Kaplan-Meier analysis the 54-month survival of our patients is 51% and one-year mortality is nearly 15%. Another study by Mehdi Nasab et al. reported a 5-year mortality rate of 37% and a one-year mortality rate of 21%, but this study calculated the mortality rate by dividing the number of deaths in five years by the total population 34   www.nature.com/scientificreports/ www.nature.com/scientificreports/ compared to our study 35 . In a systematic review and meta-analysis by Ma et al. the rate of early mortality following intertrochanteric fracture was 15.1% 36 . The in-hospital mortality rate reported in the literature ranged from 1.2 to 1.8%, which is lower than the mortality rate of our study (3.23%) 8,37,38 . It is worth noting that our hospital is a referral center, and our patients mainly come from regions with poor economic and sanitary conditions. www.nature.com/scientificreports/ Our study found that higher levels of Na are associated with an increased risk for complications in hospital. Dehydration caused by water loss is best diagnosed by serum osmolality in older people 39 . Dehydration is a major problem in the geriatrics with hip fractures. In a retrospective cohort study in 2015 the application of preoperative hemodynamic preconditioning protocol (PHP) results in lower complications for patients with hip fracture. Patients with hip fractures who were deemed at high risk for complications or mortality were treated following the PHP protocol to ensure adequate perfusion and oxygenation and to optimize hemodynamics before surgery 40 . In the study by Lindholm et al. dehydration was reported as a prognostic factor for pressure ulcers at discharge for those with hip fracture (p=0.005), however, we had only two cases of pressure ulcers 41 . In a study of 45 patients following hip fracture surgery, dehydration increased the chances of complications by nearly four times (P<0.015); Dehydrated patients presented with confusion, desaturation requiring oxygen treatment, and cardiovascular problems 42 . Our results are in contrast with a study of 8719 patients with total hip arthroplasty in which dehydration didn't show any significant relationship with 30-day complications and appears as a protective factor for 30-day readmission (P=0.001). The main difference of last study and our study is the acute setting of present study. Anemia at presentation is risk factor for 30-day readmission and those with dehydration are usually considered as non-anemic group 14 . One of the reasons could be the blood transfusion in anemic group www.nature.com/scientificreports/ in the acute setting of hip fracture which increases the infection after surgery while in the elective setting of arthroplasty administration of TXA reduces the risk of readmission 14,43 . Several limitations of study should be mentioned. The reliability and accuracy of AO/OTA classification is questionable 44 . Distribution of cases in subgroups of AO/OTA, type of implant, and type of anesthesia was unbalanced and this leads to random error. The retrospective nature of study which was conducted in one center result in selection bias. Unfortunately, because of recall bias we were not able to analyze the cause of death. The complication was an outcome with high heterogeneity which cannot be sub grouped due to unbalanced distribution of type of complication. Finally, we were not able to introduce a comorbidity index into our analysis.

Conclusion
Among different analytical factors Na before surgery as a biomarker presenting dehydration was the main prognostic factor for in hospital complications. In hospital mortality was mainly because of infection and long-term mortality was associated with blood transfusion.